Ezatiostat hydrochloride is the hydrochloride acid addition salt of ezatiostat. Ezatiostat, also known as TLK199 or TER 199, is a compound of the formula:

Ezatiostat has been shown to induce the differentiation of HL-60 promyelocytic leukemia cells in vitro, to potentiate the activity of cytotoxic agents both in vitro and in vivo, and to stimulate colony formation of all three lineages of hematopoietic progenitor cells in normal human peripheral blood. In preclinical testing, ezatiostat has been shown to increase white blood cell production in normal animals as well as in animals in which white blood cells were depleted by treatment with cisplatin or fluorouracil. Similar effects may provide a new approach to treating myelodysplastic syndrome (MDS).
Many conditions, including MDS, a form of pre-leukemia in which the bone marrow produces insufficient levels of one or more of the three major blood elements (white blood cells, red blood cells, and platelets), are characterized by depleted bone marrow. Myelosuppression, which is characterized by a reduction in blood cell levels and in a reduction of new blood cell generation in the bone marrow, is also a common, toxic effect of many standard chemotherapeutic drugs.
Ezatiostat hydrochloride in a liposomal injectable formulation was studied in a clinical trial for the treatment of MDS, and results from this trial, reported by Raza et al., J. Hem. One., 2:20 (published online 13 May 2009), demonstrated that administration of TLK199 was well tolerated and resulted in multi-lineage hematologic improvement. Ezatiostat hydrochloride in a tablet formulation has been evaluated in a clinical trial for the treatment of MDS, as reported by Raza et al., Blood, 113:6533-6540 (prepublished online 27 Apr. 2009) and a single-patient report by Quddus et al., J. Hem. One., 3:16 (published online 23 Apr. 2010), and is currently being evaluated in clinical trials for the treatment of MDS and for severe chronic idiopathic neutropenia.
It has now been discovered that, surprisingly, ezatiostat exists as a single ansolvate polymorph, form D, which demonstrates higher polymorphic stability and chemical stability compared to solvated and hydrated polymorphs of ezatiostat. See, U.S. patent application Ser. No. 13/041,136, titled “Crystalline Ezatiostat Hydrochloride Ansolvate,” filed on Mar. 4, 2011, which is incorporated herein by reference in its entirety. The stable ansolvate form is suitable for use as a tablet dosage form for therapeutic administrations of ezatiostat. See, U.S. patent application Ser. No. 13/075,116, titled “Tablet Formulation Of Ezatiostat,” filed on Mar. 29, 2011, which is incorporated herein by reference in its entirety. Given the usefulness of ezatiostat in various therapeutic applications, and the surprising discovery of a suitable ansolvate polymorph and a dosage form for its administration, there is a need to manufacture ezatiostat and ezatiostat hydrochloride ansolvate polymorph D in quantities sufficient for clinical studies and potential commercialization.
While there are reports of synthesis of ezatiostat (Lyttle et al., J. Med. Chem., 37:189-194, 1994, and U.S. Pat. No. 5,955,432), these methods use expensive protecting groups such as flurenylmethyloxycarbonyl (F-moc, see Lyttle et al., supra) or require a complex intermediate such as an oxazolidinone (U.S. Pat. No. 5,955,432, supra), which render these processes less attractive for commercial scale up.